Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following hemorrhagic shock (HS)/trauma (T), and often serves as a direct cause of patient death. Studies have shown that patients older than 65 years account for 23% of all trauma admissions, and trauma represents the fifth leading cause of death in this population. Elderly trauma patients present with significantly worse organ injury, remain in the hospital longer, require greater use of resources after discharge, and die at 3 times the rate of the younger population. Our long-term goal is to determine the aging-related mechanism that promotes ALI following HS/T, thereby potentially identifying novel targets for prophylactic intervention. We have recently demonstrated in a mouse HS model that HS upregulates expression of NOD2, a member of NOD family and the product of CARD15, in alveolar macrophages (AM) through high mobility group box 1 (HMGB1)/TLR4 signaling. Upregulated NOD2 subsequently sensitizes the AM to respond to NOD2 ligand muramyl dipeptide (MDP), a molecule derived from the bacteria wall component peptidoglycan (PGN), and this leads to augmented inflammation in the lung. More importantly, we further found that NOD2 signaling also induces autophagy in the AM, which in turn demonstrates a potent negative regulatory role in lung inflammation. Notably, this NOD2-induced AM autophagy was impaired in aged mice (20-month old), and was associated with exacerbated lung inflammation. Autophagy is an ongoing basic cell process in almost all human cell types and is upregulated by various stress conditions, including those leading to inflammation. We hypothesize that the HMGB1-TLR4-NOD2 signaling-induced autophagy in AM and neutrophils (PMN) following T/HS plays an important regulatory role in dampening lung inflammation; however, in the elderly trauma population, impaired autophagy induction in AM and PMN leads to an imbalance between pro- and counter-inflammatory factors, and thereby results in exacerbated and prolonged lung inflammation after T/HS. To test this hypothesis, we propose the following specific aims: Specific Aim 1. To determine the influence of aging-impaired autophagy on the development of post-HS lung inflammation. We will determine the role of NOD2-induced autophagy in the regulation of HS-primed lung inflammation and the influence of aging- impaired autophagy on the development of ALI. Specific Aim 2. To determine the mechanism by which aging- impaired autophagy exaggerates post-HS ALI. We will address how impaired autophagy augments lung inflammation following HS in aged mice, and whether autophagy through regulating inflammasome and/or pyroptosis alters HS-primed lung inflammation.